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NO327161B1 - Polymorphic form of clopidogrel hydrogen sulfate - Google Patents

Polymorphic form of clopidogrel hydrogen sulfate Download PDF

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NO327161B1
NO327161B1 NO20006395A NO20006395A NO327161B1 NO 327161 B1 NO327161 B1 NO 327161B1 NO 20006395 A NO20006395 A NO 20006395A NO 20006395 A NO20006395 A NO 20006395A NO 327161 B1 NO327161 B1 NO 327161B1
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hydrogen sulfate
clopidogrel hydrogen
clopidogrel
crystalline
polymorph
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Andre Bousquet
Bertrand Castro
Jean Saint-Germain
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Sanofi Aventis
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C30—CRYSTAL GROWTH
    • C30B—SINGLE-CRYSTAL GROWTH; UNIDIRECTIONAL SOLIDIFICATION OF EUTECTIC MATERIAL OR UNIDIRECTIONAL DEMIXING OF EUTECTOID MATERIAL; REFINING BY ZONE-MELTING OF MATERIAL; PRODUCTION OF A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; SINGLE CRYSTALS OR HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; AFTER-TREATMENT OF SINGLE CRYSTALS OR A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; APPARATUS THEREFOR
    • C30B7/00—Single-crystal growth from solutions using solvents which are liquid at normal temperature, e.g. aqueous solutions

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Description

Foreliggende oppfinnelse vedrører en ny polymorf av clopidogrel-hydrogensulfat eller metyl (+)-(S)-a-(2-klorfenyl)-4,5,-6,7-tetrahydro-tieno[3,2-c]pyridinyl-5-acetathydrogensulfat og en fremgangsmåte for fremstilling derav. Mer spesielt vedrører oppfinnelsen fremstillingen av denne polymorf betegnet Form 2 og isoleringen av denne forbindelse i denne nye krystallinske form, såvel som de farmasøytiske preparater som inneholder denne. The present invention relates to a new polymorph of clopidogrel hydrogen sulfate or methyl (+)-(S)-a-(2-chlorophenyl)-4,5,-6,7-tetrahydro-thieno[3,2-c]pyridinyl-5 -acetate hydrogen sulfate and a method for its production. More particularly, the invention relates to the production of this polymorphically designated Form 2 and the isolation of this compound in this new crystalline form, as well as the pharmaceutical preparations which contain it.

Clopidogrel-hydrogensulfat er et antitrombotisk middel som første gang ble beskrevet i EP 281459. Syntesernetoden som angitt i dette patent tillater fremstillingen av clopidogrel-hydrogensulf at som skal betegnes Form 1. Man har nå funnet at clopidogrel-hydrogensulfat kan eksistere i forskjellige polymorfe krystallinske former som avviker fra hverandre med hensyn til stabilitet, med hensyn til fysiske egenskaper, deres spektrale egenskaper og fremstillingsmetoder. Clopidogrel hydrogen sulfate is an antithrombotic agent that was first described in EP 281459. The synthesis method disclosed in this patent allows the preparation of clopidogrel hydrogen sulfate to be designated Form 1. It has now been found that clopidogrel hydrogen sulfate can exist in different polymorphic crystalline forms which differ from each other in terms of stability, in terms of physical properties, their spectral properties and manufacturing methods.

En av disse nye polymorfe former er således formålet med den foreliggende oppfinnelse, den er beskrevet i den foreliggende søknad og vil bli betegnet Form 2. One of these new polymorphic forms is thus the purpose of the present invention, it is described in the present application and will be designated Form 2.

Foreliggende oppfinnelse vedrører også en fremgangsmåte for fremstilling av clopidogrel-hydrogensulfat i dens polymorfe form 2. The present invention also relates to a method for the production of clopidogrel hydrogen sulphate in its polymorphic form 2.

EP-patent 281459 beskriver enantiomerer av derivater av tetrahydrotienopyridiner og av deres farmasøytisk akseptér-bare salter. EP 281459 vedrører spesifikt clopidogrel-hydrogensulf at , dvs. den høyredreiende isomer som utviser utmerkede anti-plateaggregasjonsaktivitet mens den venstre-dreiende isomer er mindre aktiv og tolereres i mindre grad. EP patent 281459 describes enantiomers of derivatives of tetrahydrothienopyridines and of their pharmaceutically acceptable salts. EP 281459 specifically relates to clopidogrel hydrogensulphate, i.e. the dextrorotatory isomer which exhibits excellent anti-platelet aggregation activity while the left-rotatory isomer is less active and less tolerated.

EP-patent 281459, som er innsendt for ti år siden, har ingen henvisning til eksistensen av spesifikke polymorfe former av clopidogrel-hydrogensulfat. Syntesen beskrevet i EP 281459 tillater fremstillingen av den polymorfe Form 1 av clopidogrel-hydrogensulf at . EP 281459 foreslår ikke forekomsten av forskjellige polymorfe former av clopidogrel eller av clopidogrel-hydrogensulfat. EP patent 281459, filed ten years ago, makes no reference to the existence of specific polymorphic forms of clopidogrel hydrogen sulfate. The synthesis described in EP 281459 allows the preparation of the polymorphic Form 1 of clopidogrel hydrogensulphate. EP 281459 does not suggest the existence of different polymorphic forms of clopidogrel or of clopidogrel hydrogen sulfate.

Ifølge læren i de ovennevnte dokumenter, fremstilles den høyredreiende isomer av clopidogrel ved saltdannelse av den racemiske forbindelse med en optisk aktiv syre som 10-L-kamfersulfonsyre i aceton etterfulgt av påfølgende rekrystal-lisering av saltet inntil et produkt med en konstant optisk rotasjon oppnås, etterfulgt av frigjøringen av den høyredrei-ende isomer fra dens salt ved hjelp av en base. Clopidogrel-hydrogensulf at oppnås deretter på konvensjonell måte ved å oppløse nevnte base i aceton avkjølt på is og med tilsetning av konsentrert svovelsyre inntil presipitering forekommer. Presipitatet som således oppnås isoleres deretter ved filtrering, vaskes og tørkes til å gi clopidogrel-hydrogensulfat i form av hvite krystaller hvis smeltepunkt er 184 °C og hvis optiske rotasjon er +55,1° (c = 1,891/CH3OH). According to the teachings of the above-mentioned documents, the dextrorotatory isomer of clopidogrel is prepared by salt formation of the racemic compound with an optically active acid such as 10-L-camphorsulfonic acid in acetone followed by subsequent recrystallization of the salt until a product with a constant optical rotation is obtained, followed by the release of the dextrorotatory isomer from its salt by means of a base. Clopidogrel hydrogensulphate is then obtained in a conventional manner by dissolving said base in acetone cooled on ice and with the addition of concentrated sulfuric acid until precipitation occurs. The precipitate thus obtained is then isolated by filtration, washed and dried to give clopidogrel hydrogen sulfate in the form of white crystals whose melting point is 184°C and whose optical rotation is +55.1° (c = 1.891/CH3OH).

Fremgangsmåtene for syntese som beskrevet i den kjente teknikk tillater kun syntesen av clopidogrel-hydrogensulfat Form 1. The methods of synthesis as described in the prior art only allow the synthesis of clopidogrel hydrogen sulfate Form 1.

Foreliggende oppfinnelse vedrører således den polymorfe form betegnet Form 2, av clopidogrel-hydrogensulfatet som, tilsvarende Form 1 av denne forbindelse, er anvendbar som et medikament for profylakse og behandling av trombose ved å virke som en plate-aggregasjonsinhibitor. Med hensyn til anvendelsen av clopidogrel og saltene derav kan man vise til Drugs of the Future 1993, 18, 2, 107 - 112. Den polymorfe Form 2 av clopidogrel-hydrogensulfat anvendes derfor som aktiv bestanddel for fremstillingen av et medikament, i kombinasjon med minst én farmasøytisk akseptérbar eksipiens, ved de samme indikasjoner som Form 1. The present invention thus relates to the polymorphic form, designated Form 2, of the clopidogrel hydrogen sulfate which, corresponding to Form 1 of this compound, is usable as a drug for the prophylaxis and treatment of thrombosis by acting as a platelet aggregation inhibitor. With regard to the use of clopidogrel and its salts, one can refer to Drugs of the Future 1993, 18, 2, 107 - 112. The polymorphic Form 2 of clopidogrel hydrogen sulfate is therefore used as an active ingredient for the production of a drug, in combination with at least one pharmaceutically acceptable excipient, for the same indications as Form 1.

Man har nå funnet at dersom clopidogrel-hydrogensulfat krystalliseres fra et løsningsmiddel er det mulig å oppnå enten den krystallinske form svarende til formen av produktet oppnådd i henhold til EP 281459 som angitt over, Form 1, eller en ny, svært stabil krystallinsk form som har en veldefinert struktur, heretter betegnet Form 2. Mer spesielt har man funnet at den nye krystallinske formen av clopidogrel-hydrogensulf at , Form 2, er minst like stabil som den Form 1 som er beskrevet og at den ikke spontant omdannes til den tidligere kjente Form 1. Videre er pulveret oppnådd fra Form 2 mer kompakt og ganske mye mindre elektrostatisk enn det oppnådd fra Form 1 og kan derfor lettere underkastes en hvilken som helst behandling under de vanlige betingelsene i forbindelse med farmakologisk teknologi dg særlig industriell galenisk farmakologi. It has now been found that if clopidogrel hydrogen sulfate is crystallized from a solvent it is possible to obtain either the crystalline form corresponding to the form of the product obtained according to EP 281459 as indicated above, Form 1, or a new, highly stable crystalline form which has a well-defined structure, hereafter referred to as Form 2. More specifically, it has been found that the new crystalline form of clopidogrel hydrogen sulfate, Form 2, is at least as stable as the Form 1 that has been described and that it does not spontaneously convert to the previously known Form 1. Furthermore, the powder obtained from Form 2 is more compact and quite a lot less electrostatic than that obtained from Form 1 and can therefore be more easily subjected to any treatment under the usual conditions in connection with pharmacological technology, particularly industrial galenic pharmacology.

Man har dessuten observert at Form 2 utviser en lavere oppløselighet enn Form 1 som resulterer fra dens høyere termodynamiske stabilitet. It has also been observed that Form 2 exhibits a lower solubility than Form 1 resulting from its higher thermodynamic stability.

Forskjellen mellom den nye krystallinske formen av clopidogrel-hydrogensulf at i henhold til den foreliggende oppfinnelse, Form 2, og Form 1 er tydelig ut fra en undersøkelse av fig. 1 til 4, mens fig. 5 til 7 viser strukturen til krystallene av Form 2. The difference between the new crystalline form of clopidogrel hydrogen sulfate according to the present invention, Form 2, and Form 1 is clear from an examination of fig. 1 to 4, while fig. 5 to 7 show the structure of the crystals of Form 2.

Fig. 1 til 7 er kjennetegnet som følger: Fig. 1 to 7 are characterized as follows:

fig. 1 angir røntgendiffraktogrammet av Form 1 av clopido grel-hydrogensulf at som pulver, fig. 1 shows the X-ray diffractogram of Form 1 of clopido grel-hydrogensulphate as powder,

fig. 2 viser røntgendiffraktogrammet av Form 2 av clopidogrel-hydrogensulf at i pulverform, fig. 2 shows the X-ray diffractogram of Form 2 of clopidogrel hydrogen sulfate in powder form,

fig. 3 viser det infrarøde spektrum av Form 2, fig. 3 shows the infrared spectrum of Form 2,

fig. 4 viser det infrarøde spektrum av Form 1, fig. 4 shows the infrared spectrum of Form 1,

- fig. 5 viser strukturformelen for clopidogrel-hydrogensulfat med nummerering av atomene i den krystallinske Form - fig. 5 shows the structural formula for clopidogrel hydrogen sulfate with numbering of the atoms in the crystalline Form

2, 2,

fig. 6 viser den romlige konformasjon av clopidogrel-hydrogensulf at , Form 2, fig. 6 shows the spatial conformation of clopidogrel hydrogen sulfate, Form 2,

fig. 7 viser stablingen av clopidogrel-hydrogensulfat, fig. 7 shows the stacking of clopidogrel hydrogen sulfate,

Form 2-molekyler i krystallgitteret. Form 2 molecules in the crystal lattice.

Ut fra de krystallografiske data er det blitt observert at den krystallinske strukturen til Form 1 inneholder to frie kationer i clopidogrel-krystallen og to frie bisulfatanioner. De to frie kationer har en tilsvarende konformasjon. Based on the crystallographic data, it has been observed that the crystalline structure of Form 1 contains two free cations in the clopidogrel crystal and two free bisulphate anions. The two free cations have a corresponding conformation.

I henhold til de krystallografiske data for Form 2, har man observert at den inneholder et fritt kation i krystall-bisulfatanion-paret. According to the crystallographic data for Form 2, it has been observed that it contains a free cation in the crystal bisulfate anion pair.

I de to formene er kationene aksialt protonert og nitrogen-atomet har R-konfigurasjon, og konformasjonen av kationene i Form 2 er forskjellige fra det som observeres i Form 1. In the two forms, the cations are axially protonated and the nitrogen atom has R configuration, and the conformation of the cations in Form 2 is different from that observed in Form 1.

I den molekylære oppstilling av de to krystallinske former er intet sete okkupert av løsningsmiddelmolekyler. In the molecular arrangement of the two crystalline forms, no seat is occupied by solvent molecules.

Oppstillingen av anionene er svært forskjellige fra den ene til den andre av de to krystallinske strukturer. Den krystallinske struktur til Form 2, av ortorombisk type, er mindre tett (1,462 g/cm<3>) enn den krystallinske struktur til Form 1 som er av monoklinisk type (1,505 g/cm3) . The arrangement of the anions is very different from one to the other of the two crystalline structures. The crystalline structure of Form 2, of the orthorhombic type, is less dense (1.462 g/cm<3>) than the crystalline structure of Form 1, which is of the monoclinic type (1.505 g/cm3).

Oppfinnelsen vedrører således en krystallinsk (+)-(S)-polymorf av clopidogrel-hydrogensulfat (Form 2), som er kjennetegnet ved at dens pulver-røntgendiffraktogram viser de etterfølgende karakteristiske topper uttrykt som interplanare avstander ved omtrent 4,11, 6,86, 3,60, 5,01, 3,74, 6,49, 5,66 Å. The invention thus relates to a crystalline (+)-(S)-polymorph of clopidogrel hydrogen sulfate (Form 2), which is characterized in that its powder X-ray diffractogram shows the following characteristic peaks expressed as interplanar distances at about 4.11, 6.86 , 3.60, 5.01, 3.74, 6.49, 5.66 Å.

I henhold til et annet aspekt er formålet med oppfinnelsen også en fremgangsmåte for fremstilling av clopidogrel-hydrogensulf at Form 2 hvor: (a) metyl (+)-(S)-a-(2-klorfenyl)-4,5,6,7-tetrahydro-tieno[3,2-c]pyridinyl-5-acetatkamfersulfonat oppløses i According to another aspect, the purpose of the invention is also a method for the production of clopidogrel hydrogen sulfate Form 2 where: (a) methyl (+)-(S)-a-(2-chlorophenyl)-4,5,6, 7-tetrahydro-thieno[3,2-c]pyridinyl-5-acetate camphor sulfonate is dissolved in

et organisk løsningsmiddel, an organic solvent,

(b) kamfersulfonsyre ekstraheres med en vandig alkalisk (b) camphor sulphonic acid is extracted with an aqueous alkaline

oppløsning av kaliumkarbonat og vaskes med vann, solution of potassium carbonate and washed with water,

(c) den organiske fase konsentreres under vakuum og (c) the organic phase is concentrated under vacuum and

konsentrasjonsresten tas opp i aceton, the concentration residue is taken up in acetone,

(d) 80 % svovelsyre tilsettes, (d) 80% sulfuric acid is added,

(e) blandingen oppvarmes med tilbakeløp, produktet krystalliseres, blandingen avkjøles, filtreres og krystallene vaskes og tørkes deretter under redusert (e) the mixture is heated at reflux, the product is crystallized, the mixture is cooled, filtered and the crystals are washed and then dried under reduced

trykk til å gi clopidogrel-hydrogensulfat Form 1, pressure to give clopidogrel hydrogen sulfate Form 1,

(f) de oppnådde vandige-acetonholdige modervæsker frigjør deretter, etter 3 til 6 måneder, krystaller av clopidogrel-hydrogensulf at Form 2. (f) the obtained aqueous-acetone mother liquors then release, after 3 to 6 months, crystals of clopidogrel hydrogen sulfate Form 2.

Den foreliggende oppfinnelse vedrører således en fremgangsmåte for fremstilling av (+)-(S)-clopidogrel-hydrogensulfat Form 2, som er kjennetegnet ved at de vandige acetonholdige modervæsker resulterende fra krystalliseringen av (+)-(S)-clopidogrel-hydrogensulfat Form 1 underkastes utsalting for å oppnå, etter 3 til 6 måneder, krystaller av clopidogrel-hydrogensulf at Form 2. The present invention thus relates to a method for the production of (+)-(S)-clopidogrel hydrogen sulfate Form 2, which is characterized in that the aqueous acetone-containing mother liquors resulting from the crystallization of (+)-(S)-clopidogrel hydrogen sulfate Form 1 subjected to salting out to obtain, after 3 to 6 months, crystals of clopidogrel hydrogensulphate Form 2.

De vandige-acetonholdige modervæsker resulterende fra krystalliseringen av ( + )-(S)-clopidogrel-hydrogensulfat Form 1 inneholder fra 0,3 til 1 % vann. The aqueous-acetone mother liquors resulting from the crystallization of ( + )-(S)-clopidogrel hydrogen sulfate Form 1 contain from 0.3 to 1% water.

De inneholder opptil omtrent 10 % clopidogrel-hydrogensulfat, hvor denne mengde beregnes fra mengden metyl (+)-(S)-a-(2-klorfenyl)-4,5,67-tetrahydrotieno[3,2-c]pyridinyl-5-acetatkamfersulfonat som anvendes under omdannelsen til hydrogensulfat. They contain up to about 10% clopidogrel hydrogen sulfate, this amount being calculated from the amount of methyl (+)-(S)-a-(2-chlorophenyl)-4,5,67-tetrahydrothieno[3,2-c]pyridinyl-5 -acetate camphor sulphonate which is used during the conversion to hydrogen sulphate.

Disse vandige acetonholdige modervæsker frigjør sakte, etter en periode på 3 til 6 måneder, ved en temperatur som er mindre enn 40 °C, clopidogrel-hydrogensulfat Form 2. These aqueous acetone-containing mother liquors slowly release, after a period of 3 to 6 months, at a temperature less than 40 °C, clopidogrel hydrogen sulfate Form 2.

I henhold til et annet aspekt vedrører den foreliggende oppfinnelse en annen fremgangsmåte for fremstilling av clopidogrel-hydrogensulf at Form 2 hvor: (a) metyl (+)-(S)-a-(2-klorfenyl)-4,5,6,7-tetrahydrotieno-[3,2-c]pyridinyl-5-acetatkamfersulfonat oppløses i et organisk løsningsmiddel, (b) kamfersulfonsyre ekstraheres med en vandig alkalisk oppløsning av kaliumkarbonat og vaskes med vann, (c) den organiske fase konsentreres under vakuum og According to another aspect, the present invention relates to another method for the production of clopidogrel hydrogen sulfate Form 2 where: (a) methyl (+)-(S)-a-(2-chlorophenyl)-4,5,6, 7-tetrahydrothieno-[3,2-c]pyridinyl-5-acetate camphorsulfonate is dissolved in an organic solvent, (b) camphorsulfonic acid is extracted with an aqueous alkaline solution of potassium carbonate and washed with water, (c) the organic phase is concentrated under vacuum and

konsentrasjonsresten tas opp i aceton, the concentration residue is taken up in acetone,

som er kjennetegnet ved at 94 - 96 % svovelsyre tilsettes og at blandingen podes med clopidogrel-hydrogensulfat Form 2, produktet krystalliseres, blandingen avkjøles, filtreres og krystallene vaskes og tørkes deretter under redusert trykk til å gi clopidogrel-hydrogensulfat Form 2. which is characterized by the addition of 94 - 96% sulfuric acid and the inoculation of the mixture with clopidogrel hydrogen sulfate Form 2, the product crystallized, the mixture cooled, filtered and the crystals washed and then dried under reduced pressure to give clopidogrel hydrogen sulfate Form 2.

Svovelsyren som tilsettes har en temperatur på 2 0°C. The sulfuric acid that is added has a temperature of 20°C.

Et annet alternativ omfatter å underkaste den krystallinske suspensjon for mekanisk skjærkraft ved hjelp av en skjærkraft-anordning. Denne anordning kan nå en rotasjonshastig-het på omtrent 10 000 til 15 000 omdreininger per minutt. Anordningen med disse egenskaper er f.eks. av Turrax-typen som er markedsført av IKA-Werke (DE). Disse anordninger er dessuten egnet for behandling av industrielle kvantiteter. Another alternative comprises subjecting the crystalline suspension to mechanical shear by means of a shearing device. This device can reach a rotational speed of approximately 10,000 to 15,000 revolutions per minute. The device with these properties is e.g. of the Turrax type marketed by IKA-Werke (DE). These devices are also suitable for processing industrial quantities.

Det viktigste er å oppnå, ved maling, fine partikler fra en basisoppløsning som kun inneholder en fraksjon av den totale svovelsyren. Den resterende del vil deretter innhelles sakte for å fremme krystallvekst. Forsøk ble gjennomført hvor man startet med 10 % av den nødvendige svovelsyre som ble helt inn i begynnelsen. The most important thing is to obtain, in painting, fine particles from a base solution containing only a fraction of the total sulfuric acid. The remaining portion will then be poured in slowly to promote crystal growth. Experiments were carried out where one started with 10% of the required sulfuric acid which was poured in at the beginning.

Den krystallinske polymorf av clopidogrel-hydrogensulfat Form 2 ifølge oppfinnelsen har mere spesielt en pulver-røntgen-dif f raksjonsprof il som angitt i tabell I. The crystalline polymorph of clopidogrel hydrogen sulfate Form 2 according to the invention has more particularly a powder X-ray diffraction profile as indicated in Table I.

Mere spesielt er Form 2 også kjennetegnet ved et smeltepunkt som bestemt ved differensialentalpianalyse (DSC) på 176 °C og ved karakteristisk absorpsjoner i det infrarøde området og i det nær-infrarøde området. More particularly, Form 2 is also characterized by a melting point as determined by differential thermal analysis (DSC) of 176 °C and by characteristic absorptions in the infrared range and in the near-infrared range.

Enkelte fysiske egenskaper og opptredenen til den nye krystallinske form av clopidogrel-hydrogensulfat ifølge oppfinnelsen er helt forskjellige fra dem for Form 1, noe som er vist ved å undersøke de to former ved hjelp av konvensjonelle metoder og teknikker. Certain physical properties and the behavior of the new crystalline form of clopidogrel hydrogen sulfate according to the invention are completely different from those of Form 1, as shown by examining the two forms using conventional methods and techniques.

Røntgendiffraksjonsprofilen for pulveret (diffraksjonsvinkel) ble etablert med et Siemens D500TT-diffraktometer. De karakteristiske pulver-diffraktogrammer mellom 2 og 4 0° ved Bragg 20 (2 theta, grader, for CuKa, A=l,542 Å) er angitt i fig. 1 for Form 1 og i fig. 2 for Form 2. De signifikante linjer i fig. 1 er samlet i tabell II, mens de i fig. 2 er samlet i tabell I. The X-ray diffraction profile of the powder (diffraction angle) was established with a Siemens D500TT diffractometer. The characteristic powder diffractograms between 2 and 40° at Bragg 20 (2 theta, degrees, for CuKa, A=1.542 Å) are indicated in fig. 1 for Form 1 and in fig. 2 for Form 2. The significant lines in fig. 1 are collected in table II, while those in fig. 2 are collected in table I.

I tabeller I og II er d inter-gitter avstanden og I/I0 repre-senterer den relative intensitet uttrykt som en prosentandel av den mest intense linje. In Tables I and II, d is the inter-grating distance and I/I0 represents the relative intensity expressed as a percentage of the most intense line.

Differensialentalpianalyse (DSC) av Former 1 og 2 ble gjen-nomført for sammenligningsformål ved anvendelse av et Perkin Eimer DSC 7-apparat som er kalibrert med henvisning til indium. For den kalorimetriske analyse ble det anvendt 2,899 mg av Form 1 eller 2,574 mg av Form 2 som oppnådd i eksempel 2 i et bølget og perforert aluminiumsbeger, i et temperatur-område fra 40 til 230 °C og ved en oppvarmingshastighet på 10 °C/minutt. Smeltepunktet og fusjonsentalpien er indikert i tabell III. Smeltepunktet svarer til den karakteristiske smeltetemperatur oppnådd ved hjelp av DSC. Denne verdi kan også defineres til å være den temperatur som svarer til skjæringspunktet mellom basislinjen og tangenten til den stigende topp for smelter observert ved DSC. Differential enthalpy analysis (DSC) of Forms 1 and 2 was performed for comparative purposes using a Perkin Eimer DSC 7 apparatus calibrated with reference to indium. For the calorimetric analysis, 2.899 mg of Form 1 or 2.574 mg of Form 2 as obtained in Example 2 were used in a corrugated and perforated aluminum beaker, in a temperature range from 40 to 230 °C and at a heating rate of 10 °C/ minute. The melting point and enthalpy of fusion are indicated in Table III. The melting point corresponds to the characteristic melting temperature obtained by DSC. This value can also be defined to be the temperature corresponding to the intersection between the baseline and the tangent to the rising peak for melts observed by DSC.

Forskjellen mellom den nye Form 2 og Form 1 av clopidogrel-hydrogensulf at ble også vist ved infrarød spektroskopi. Fourier Transform IR (FTIR)-spektrene ble oppnådd med et Perkin Eimer-system 2000 spektrometer med en oppløsning på 4 cm"<1> fra 4000 cm"<1> til 400 cm"<1>. Prøvene tilveiebringes i form av pelleter av KBr ved 0,3 % som Form 1 eller som Form 2. Pelleten ble komprimert ved 10 tonn i 2 minutter. Hver prøve ble undersøkt etter 4 akkumuleringer. The difference between the new Form 2 and Form 1 of clopidogrel hydrogensulphate was also shown by infrared spectroscopy. The Fourier Transform IR (FTIR) spectra were obtained with a Perkin Eimer System 2000 spectrometer with a resolution of 4 cm"<1> from 4000 cm"<1> to 400 cm"<1>. The samples are provided in the form of pellets of KBr at 0.3% as Form 1 or as Form 2. The pellet was compressed at 10 tons for 2 minutes.Each sample was examined after 4 accumulations.

Sammenligning av de karakteristiske linjer uttrykt i bølge-lengde (i cm"<1>) og av intensitet (som prosentandel av transmittans) er illustrert i tabell IV. Comparison of the characteristic lines expressed in wavelength (in cm"<1>) and of intensity (as a percentage of transmittance) is illustrated in Table IV.

Det fremgår klart fra tabell IV at Form 2 utviser karakteristiske absorpsjoner ved 2551 cm"<1>, 1497 cm"<1>, 1189 cm"1 og 1029 cm"<1> som er fraværende fra Form 1. It is clear from Table IV that Form 2 exhibits characteristic absorptions at 2551 cm"<1>, 1497 cm"<1>, 1189 cm"1 and 1029 cm"<1> which are absent from Form 1.

Den spesielle strukturen til pulveret av Form 2 ble vist ved analyse av monokrystallen ved røntgendiffraksjon av pulveret ved anvendelse av et MSC-Rigaka AFC6S diffraktometer og SHELXS-90 og SHELXS-93 software på en SG IRIS Indigo arbeids-stasjon. Posisjonen av C-H-hydrogenene ble generert i en avstand på 0,95 Å. De krystallografiske data, særlig inter-planaravstandene (a, b, c), vinklene (a, p, y) og volumet av hver enhetscelle er indikert i tabell V. The particular structure of the powder of Form 2 was shown by analysis of the single crystal by X-ray diffraction of the powder using an MSC-Rigaka AFC6S diffractometer and SHELXS-90 and SHELXS-93 software on an SG IRIS Indigo workstation. The position of the C-H hydrogens was generated at a distance of 0.95 Å. The crystallographic data, in particular the inter-planar distances (a, b, c), the angles (a, p, y) and the volume of each unit cell are indicated in Table V .

Atom-koordinatene for Form 2 er angitt i tabell VI, lengden av bindingene i tabell VII, vinklene mellom bindingene i tabell VIII og de karakteristiske dreiningsvinklene i tabell IX. The atomic coordinates for Form 2 are given in Table VI, the lengths of the bonds in Table VII, the angles between the bonds in Table VIII and the characteristic torsion angles in Table IX.

Avstandene er i Ångstrøm. Standardavvikene estimert på desimalen er i parenteser. Vinklene er i grader. Standardavvikene estimert på den siste desimalen er i parenteser. Vinklene er i grader. Standardavvikene estimert på den siste desimalen er i parenteser. The distances are in Ångstrøm. The standard deviations estimated at the decimal point are in parentheses. Angles are in degrees. The standard deviations estimated at the last decimal place are in parentheses. Angles are in degrees. The standard deviations estimated at the last decimal place are in parentheses.

Tegnet er positivt dersom, når man ser fra atom 2 til atom 3, atom 1 vil legge seg oppå atom 4 gjennom en bevegelse med urviserne. The sign is positive if, when looking from atom 2 to atom 3, atom 1 will lie on top of atom 4 through a clockwise movement.

Røntgenkrystallografistudier, særlig krystallografidataene i tabell I, atom-koordinatene i tabell VI, bindingslengden i tabell VII, vinklene mellom bindingene i tabell VIII og de karakteristiske dreiningsvinklene i tabell IX gir bevis på den foreslåtte struktur som illustrert i fig. 5 og 6. X-ray crystallographic studies, particularly the crystallographic data in Table I, the atomic coordinates in Table VI, the bond length in Table VII, the angles between the bonds in Table VIII and the characteristic torsion angles in Table IX provide evidence of the proposed structure as illustrated in Fig. 5 and 6.

Undersøkelser under et mikroskop viste at krystallene av den nye Form 2 er morfologisk forskjellige fra dem til Form 1. Examinations under a microscope showed that the crystals of the new Form 2 are morphologically different from those of Form 1.

Krystallene av Form 1 eksisterer i form av irregulære plater, mens krystallene av Form 2 eksisterer i form av agglomerater. The crystals of Form 1 exist in the form of irregular plates, while the crystals of Form 2 exist in the form of agglomerates.

I kraft av dens lave elektrostatisitet sammenlignet med den til Form 1, er den derfor særlig egnet for fremstilling av farmasøytisk preparater for behandling av en hvilken som helst sykdom hvor et anti-trombotisk middel er indikert. By virtue of its low electrostaticity compared to that of Form 1, it is therefore particularly suitable for the manufacture of pharmaceutical preparations for the treatment of any disease where an anti-thrombotic agent is indicated.

Således, ifølge et annet av aspektene, vedrører den foreliggende oppfinnelse også farmasøytiske preparater som inneholder, som aktiv bestanddel, clopidogrel-hydrogensulfat Form 2 som er kjennetegnet ved en pulver-røntgendiffraksjonsprofil som illustrert i tabell I, i kombinasjon med minst ett farmasøytisk hjelpestoff. Thus, according to another of the aspects, the present invention also relates to pharmaceutical preparations containing, as active ingredient, clopidogrel hydrogen sulfate Form 2 which is characterized by a powder X-ray diffraction profile as illustrated in Table I, in combination with at least one pharmaceutical excipient.

Clopidogrel-hydrogensulfat Form 2 ifølge oppfinnelsen er foretrukket utformet i farmasøytiske preparater for oral administrering som inneholder 75 mg aktiv bestanddel per doseringsenhet, i form av en blanding med minst ett farmasøytisk hjelpestoff. Clopidogrel hydrogen sulfate Form 2 according to the invention is preferably formulated in pharmaceutical preparations for oral administration that contain 75 mg of active ingredient per dosage unit, in the form of a mixture with at least one pharmaceutical excipient.

Når et fast preparat i form av tabletter fremstilles, blandes den prinsipale aktive bestanddel med en farmasøytisk bærer, som gelatin, stivelse, laktose, magnesiumstearat, talkum, gummi arabicum og lignende. Tablettene kan belegges med sukrose eller andre passende substanser eller de kan alternativt prosessere slik at de har en forlenget eller utsatt aktivitet eller de frigjør kontinuerlig en for-håndsbestemt mengde av aktiv bestanddel. When a solid preparation in the form of tablets is prepared, the principal active ingredient is mixed with a pharmaceutical carrier, such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic and the like. The tablets can be coated with sucrose or other suitable substances or they can alternatively be processed so that they have a prolonged or delayed activity or they continuously release a predetermined amount of active ingredient.

Et preparat i form av gelatinkapsler oppnås ved å blande den aktive bestanddel med et fortynningsmiddel og helle den oppnådde blanding inn i myke eller harde gelatinkapsler. A preparation in the form of gelatin capsules is obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.

Pulverne eller granulene som er dispergérbare i vann kan inneholde den aktive bestanddel i form av en blanding med dispersjonsmidler eller fuktemidler, eller suspensjonsmidler, som polyvinylpyrrolidon, såvel som søtningsstoffer eller smakskorrigerende midler. The powders or granules which are dispersible in water may contain the active ingredient in the form of a mixture with dispersing agents or wetting agents, or suspending agents, such as polyvinylpyrrolidone, as well as sweetening agents or flavor correcting agents.

Dersom det er ønskelig å utforme den aktive bestanddel for rektal administrering, anvendes stikkpiller som fremstilles med bindemidler som smelter ved rektumtemperaturen, f.eks. kakaosmør eller polyetylenglykol. If it is desired to formulate the active ingredient for rectal administration, suppositories are used which are produced with binders which melt at the rectal temperature, e.g. cocoa butter or polyethylene glycol.

For parenterale administreringer anvendes vandige suspen-sjoner i form av saltoppløsninger eller sterile og injisér-bare oppløsninger. For parenteral administrations, aqueous suspensions in the form of saline solutions or sterile and injectable solutions are used.

Den aktive bestanddel kan også utformes som mikrokapsler, eventuelt med én eller flere bærere eller tilsetningsstoffer. The active ingredient can also be designed as microcapsules, possibly with one or more carriers or additives.

De etterfølgende eksempler skal illustrere oppfinnelsen. The following examples shall illustrate the invention.

Fremstilling av metyl (+)-(S)-a-(2-klorfenyl)-4,5,6-7-tetrahydrotieno[3,2-c]pyridinyl-5-acetatkamfersulfonat Preparation of methyl (+)-(S)-α-(2-chlorophenyl)-4,5,6-7-tetrahydrothieno[3,2-c]pyridinyl-5-acetate camphor sulfonate

400 kg racemisk metyl a-(2-klorfenyl)-4,5,6-7-tetrahydro-tieno[3,2-c]pyridinyl-5-acetathydroklorid og 1840 kg diklormetan innføres i en omrørt reaktor. 12 00 kg av en vandig 8 % natriumbikarbonatoppløsning tilsettes deretter sakte. Etter bunnfelling konsentreres den organiske fase under vakuum. 400 kg of racemic methyl α-(2-chlorophenyl)-4,5,6-7-tetrahydro-thieno[3,2-c]pyridinyl-5-acetate hydrochloride and 1840 kg of dichloromethane are introduced into a stirred reactor. 1200 kg of an aqueous 8% sodium bicarbonate solution is then slowly added. After settling, the organic phase is concentrated under vacuum.

Konsentrasjonsresten fortynnes med 1000 liter aceton. En oppløsning av 154 kg 1 R-10 kamfersulfonsyre i 62 0 liter aceton tilsettes ved 20 - 25 °C. Metyl a-(2-klorfenyl)-4,5, 6-7-tetrahydrotieno[3,2-c]pyridinyl-5-acetatkamfer-sulf onat avkjøles og krystalliseres med anvendelse av kim-krystall, om nødvendig. Når krystalliseringen er rikelig, oppvarmes blandingen med tilbakeløp og avkjøles til 2 5 °C. Krystallene filtreres deretter og vaskes med aceton og tørkes deretter under redusert trykk. 196 kg metyl ( + ) - (S)-cc-(2-klorfenyl)-4,5,6-7-tetrahydrotieno[3,2-c]pyridinyl-5-acetat-kamf ersulf onat oppnås således, som er et utbytte på 33 %. The concentration residue is diluted with 1000 liters of acetone. A solution of 154 kg 1 R-10 camphorsulphonic acid in 620 liters of acetone is added at 20 - 25 °C. Methyl α-(2-chlorophenyl)-4,5,6-7-tetrahydrothieno[3,2-c]pyridinyl-5-acetate camphor sulfonate is cooled and crystallized using seed crystal, if necessary. When crystallization is abundant, the mixture is refluxed and cooled to 25 °C. The crystals are then filtered and washed with acetone and then dried under reduced pressure. 196 kg of methyl ( + ) - (S)-cc-(2-chlorophenyl)-4,5,6-7-tetrahydrothieno[3,2-c]pyridinyl-5-acetate-camphor sulfonate is thus obtained, which is a dividend of 33%.

Fremstilling av clopidogrel-hydrogensulfat Form 2. Preparation of clopidogrel hydrogen sulfate Form 2.

EKSEMPEL IA EXAMPLE IA

1200 kg clopidogrel-kamfersulfonat fremstilt som indikert i det foregående innføres i en 6000-liters reaktor, under nitrogen. 2345 liter diklormetan tilsettes og reaksjonsblandingen omrøres i 3 0 minutter til 1 time. Deretter inn-føres en oppløsning av 214,5 kg kaliumkarbonat oppløst i 1827 liter deionisert vann. Den organiske fase trekkes ut og den vandige fase vaskes flere ganger med diklormetan. De organiske faser kombineres og konsentreres under vakuum. Aceton tilsettes til konsentratet og blandingen filtreres på en filterpatron på 0,1 /i til 1 /z. Acetonoppløsningen (3033 liter) inneholdende basen innføres i en reaktor under nitrogen og 264,8 kg av en 80 % svovelsyreoppløsning tilsettes deretter ved 2 0 °C. 1200 kg of clopidogrel camphor sulphonate prepared as indicated above is introduced into a 6000 liter reactor, under nitrogen. 2345 liters of dichloromethane are added and the reaction mixture is stirred for 30 minutes to 1 hour. A solution of 214.5 kg of potassium carbonate dissolved in 1827 liters of deionised water is then introduced. The organic phase is extracted and the aqueous phase is washed several times with dichloromethane. The organic phases are combined and concentrated under vacuum. Acetone is added to the concentrate and the mixture is filtered on a filter cartridge of 0.1 /i to 1 /z. The acetone solution (3033 liters) containing the base is introduced into a reactor under nitrogen and 264.8 kg of an 80% sulfuric acid solution is then added at 20°C.

Løsningsmidlet avdestilleres, blandingen avkjøles til en temperatur fra 0 til -5 °C og krystallene separeres ved filtrering på en Biichnertrakt for å oppnå, etter tørking, 779,1 kg clopidogrel-hydrogensulfat Form 1, sm.p. = 184 + 3 The solvent is distilled off, the mixture is cooled to a temperature of from 0 to -5 °C and the crystals are separated by filtration on a Biichner funnel to obtain, after drying, 779.1 kg of clopidogrel hydrogen sulfate Form 1, m.p. = 184 + 3

De oppnådde vandige acetonholdige modervæsker med en temperatur på mindre enn 4 0 °C frigjør deretter, etter 3 til 6 måneder, krystaller av clopidogrel-hydrogensulfat Form 2, sm.p. = 176 ± 3 °C. The obtained aqueous acetone-containing mother liquors with a temperature of less than 40 °C then release, after 3 to 6 months, crystals of clopidogrel hydrogen sulfate Form 2, m.p. = 176 ± 3 °C.

EKSEMPEL IB EXAMPLE IB

12 00 kg clopidogrel-kamfersulfonat fremstilt som indikert i det foregående innføres i en 6000-liters reaktor under nitrogen, 2345 liter diklometan tilsettes og reaksjonsblandingen omrøres i fra 3 0 minutter til 1 time. Deretter innføres en oppløsning av 214,5 kg kaliumkarbonat oppløst i 182 7 liter deionisert vann. Den organiske fase trekkes ut og den vandige fase vaskes flere ganger med diklormetan. De organiske faser kombineres og konsentreres under vakuum. Aceton tilsettes til konsentratet og blandingen filtreres på en filterpatron på fra 0,1 /i til 1 /x. Acetonoppløsningen (3033 liter) inneholdende basen innføres i en reaktor under nitrogen og 264,8 kg av en 96 % svovelsyreoppløsning tilsettes deretter ved 20 °C. 1200 kg of clopidogrel-camphor sulfonate prepared as indicated above is introduced into a 6000 liter reactor under nitrogen, 2345 liters of dichloromethane is added and the reaction mixture is stirred for from 30 minutes to 1 hour. A solution of 214.5 kg of potassium carbonate dissolved in 182 7 liters of deionized water is then introduced. The organic phase is extracted and the aqueous phase is washed several times with dichloromethane. The organic phases are combined and concentrated under vacuum. Acetone is added to the concentrate and the mixture is filtered on a filter cartridge of from 0.1 µl to 1 µl. The acetone solution (3033 liters) containing the base is introduced into a reactor under nitrogen and 264.8 kg of a 96% sulfuric acid solution is then added at 20°C.

Løsningsmidlet avdestilleres, blandingen avkjøles til en temperatur fra 0 til -5 °C og krystallene separeres ved filtrering på en Biichnertrakt for å oppnå, etter tørking, 785,3 kg clopidogrel-hydrogensulfat Form 1, sm.p. = 184 + 3 The solvent is distilled off, the mixture is cooled to a temperature of from 0 to -5 °C and the crystals are separated by filtration on a Biichner funnel to obtain, after drying, 785.3 kg of clopidogrel hydrogen sulfate Form 1, m.p. = 184 + 3

De oppnådde vandige-acetonholdige modervæsker frigjør deretter, etter 3 til 6 måneder, ved en temperatur på mindre enn 40 °C, krystaller av clopidogrel-hydrogensulfat Form 2, sm.p. = 176 ± 3 °C. The obtained aqueous-acetone mother liquors then release, after 3 to 6 months, at a temperature of less than 40°C, crystals of clopidogrel hydrogen sulfate Form 2, m.p. = 176 ± 3 °C.

EKSEMPEL 2 EXAMPLE 2

909 liter diklormetan og 405 kg metyl ( + )- (S)-a-(2-klorfenyl)-4,5,6-7-tetrahydrotieno[3,2-c]pyridinyl-5-acetatkamfersulfonat innføres i en reaktor. Kamfersulfonsyren ekstraheres med en vandig oppløsning av 80 kg kaliumkarbonat i 680 liter vann. Den organiske fase vaskes deretter med vann. Diklormetanen konsentreres og konsentrasjonsresten tas opp i 1140 liter aceton. 100 kg 96 % svovel- 909 liters of dichloromethane and 405 kg of methyl ( + )-(S)-a-(2-chlorophenyl)-4,5,6-7-tetrahydrothieno[3,2-c]pyridinyl-5-acetate camphor sulphonate are introduced into a reactor. The camphor sulphonic acid is extracted with an aqueous solution of 80 kg of potassium carbonate in 680 liters of water. The organic phase is then washed with water. The dichloromethane is concentrated and the concentration residue is taken up in 1140 liters of acetone. 100 kg 96% sulfur

syre tilsettes deretter ved 20 °C. Blandingen podes med 0,3 kg clopidogrel-hydrogensulfat Form 2 oppnådd i henhold til eksempel IA eller IB. Clopidogrel-hydrogensulfatet utkry-stalliseres. Materialet filtreres og vaskes deretter med aceton og tørkes under redusert trykk. 310 kg clopidogrel-hydrogensulf at Form 2 oppnås, som er et utbytte på 90,9 %, sm.p. = 176 ± 3 °C. acid is then added at 20 °C. The mixture is inoculated with 0.3 kg of clopidogrel hydrogen sulfate Form 2 obtained according to example IA or IB. The clopidogrel hydrogen sulfate crystallizes out. The material is filtered and then washed with acetone and dried under reduced pressure. 310 kg of clopidogrel hydrogen sulph at Form 2 is obtained, which is a yield of 90.9%, m.p. = 176 ± 3 °C.

EKSEMPEL 3 EXAMPLE 3

909 liter diklormetan og 450 kg metyl (+)-(S)- a-(2-klor-fenyl)-4,5,6-7-tetrahydrotieno[3,2-c]pyridinyl-5-acetatkamfersulfonat innføres i en reaktor. Kamfersulfonsyren ekstraheres med en vandig oppløsning av 80 kg kaliumkarbonat i 680 liter vann. Den organiske fase vaskes deretter med vann. Diklormetanet konsentreres og konsentrasjonsresten tas opp i 1296 liter aceton. 909 liters of dichloromethane and 450 kg of methyl (+)-(S)-α-(2-chloro-phenyl)-4,5,6-7-tetrahydrothieno[3,2-c]pyridinyl-5-acetate camphor sulfonate are introduced into a reactor . The camphor sulphonic acid is extracted with an aqueous solution of 80 kg of potassium carbonate in 680 liters of water. The organic phase is then washed with water. The dichloromethane is concentrated and the concentration residue is taken up in 1296 liters of acetone.

Temperaturen stabiliserer seg ved 2 0 °C og Turrax skrus på. 10 % av mengden av 94 - 96 % svovelsyre (8,3 kg) tilsettes deretter i løpet av noen få minutter. Blandingen podes med 0,012 kg clopidogrel-hydrogensulfat Form 2 oppnådd ifølge eksempel IA eller IB. Clopidogrel-hydrogensulfonatet ut-krystalliseres. Reaksjonsblandingen forblir under innvirk-ningen av Turrax i 45 minutter. De resterende 90 % av 94 - 96 % svovelsyren (74,6 kg) ihelles deretter i løpet av 2 timer, mens Turraxen holdes i drift. Turraxen stanses 30 minutter etter endt tilsetning av syre og blandingen omrøres i 30 minutter ved 2 0 °C. Den filtreres, vaskes med aceton og tørkes under redusert trykk. The temperature stabilizes at 20 °C and the Turrax is switched on. 10% of the amount of 94 - 96% sulfuric acid (8.3 kg) is then added over a few minutes. The mixture is inoculated with 0.012 kg of clopidogrel hydrogen sulfate Form 2 obtained according to example IA or IB. The clopidogrel hydrogen sulphonate crystallizes out. The reaction mixture remains under the influence of Turrax for 45 minutes. The remaining 90% of the 94 - 96% sulfuric acid (74.6 kg) is then poured over the course of 2 hours, while the Turrax is kept in operation. The turrax is stopped 30 minutes after the end of the addition of acid and the mixture is stirred for 30 minutes at 20 °C. It is filtered, washed with acetone and dried under reduced pressure.

310 kg clopidogrel-hydrogensulfonat Form 2 oppnås, som er et utbytte på 90,9 %, sm.p. = 176 ± 3 °C. 310 kg of clopidogrel hydrogensulfonate Form 2 is obtained, which is a yield of 90.9%, m.p. = 176 ± 3 °C.

Claims (11)

1. Krystallinsk (+)-(S)-polymorf av clopidogrel-hydrogensulf at (Form 2), karakterisert ved at dens pulver-røntgendiffraktogram viser de etterfølgende karakteristiske topper uttrykt som interplanare avstander ved omtrent 4,11, 6,86, 3,60, 5,01, 3,74, 6,49, 5,66 Å.1. Crystalline (+)-(S) polymorph of clopidogrel hydrogen sulfate (Form 2), characterized in that its powder X-ray diffractogram shows the following characteristic peaks expressed as interplanar distances at about 4.11, 6.86, 3.60, 5.01, 3.74, 6.49, 5.66 Å. 2. Krystallinsk (+)-(S)-polymorf av clopidogrel-hydrogensulf at (Form 2) som angitt i krav 1, hvor dens infrarøde spekter utviser karakteristiske absorpsjoner som uttrykt i cm-<1> ved: 2551, 1497, 1189 og 1029, med respektive transmittans-prosentandeler på omtrent: 43, 63,7, 18, 33,2.2. Crystalline (+)-(S)-polymorph of clopidogrel hydrogen sulfate (Form 2) as set forth in claim 1, wherein its infrared spectrum exhibits characteristic absorptions as expressed in cm-<1> at: 2551, 1497, 1189 and 1029, with respective transmittance percentages of approximately: 43, 63.7, 18, 33.2. 3. Krystallinsk (+)-(S)polymorf av clopidogrel-hydrogensulf at (Form 2) som angitt i krav 1, som har et smeltepunkt på 176 + 3 °C.3. Crystalline (+)-(S) polymorph of clopidogrel hydrogen sulfate (Form 2) as set forth in claim 1, having a melting point of 176 + 3 °C. 4. Krystallinsk polymorf av clopidogrel-hydrogensulfat (Form 2) som angitt i krav 1 og 2, som har et pulver-røntgen-dif f raktogram som følger:4. Crystalline polymorph of clopidogrel hydrogen sulfate (Form 2) as set forth in claims 1 and 2, having a powder X-ray diffractogram as follows: 5. Krystallinsk polymorf av clopidogrel-hydrogensulfat (Form 2) som angitt i krav 1 og 2, som har et infrarødt spekter som . følger:5. Crystalline polymorph of clopidogrel hydrogen sulfate (Form 2) as set forth in claims 1 and 2, which has an infrared spectrum as . following: 6. Fremgangsmåte for fremstilling av (+)-(S)-clopidogrel-hydrogensulfat (Form 2) som angitt i krav 1, 2 og 3, karakterisert ved at: de vandige acetonholdige modervæsker resulterende fra krystalliseringen av (+)-(S)-clopidogrel-hydrogensulfat Form 1 underkastes utsalting for å oppnå, etter 3 til 6 måneder, krystaller av clopidogrel-hydrogensulfat Form 2.6. Process for the production of (+)-(S)-clopidogrel hydrogen sulfate (Form 2) as stated in claims 1, 2 and 3, characterized in that: the aqueous acetone-containing mother liquors resulting from the crystallization of (+)-(S) -clopidogrel hydrogen sulfate Form 1 is subjected to salting out to obtain, after 3 to 6 months, crystals of clopidogrel hydrogen sulfate Form 2. 7. Fremgangsmåte som angitt i krav 6, hvor de vandige acetonholdige modervæsker som resulterer fra krystalliseringen av (+)-(S)clopidogrel-hydrogensulfat Form 1 inneholder 0,3 til 1 % vann.7. Process as set forth in claim 6, wherein the aqueous acetone-containing mother liquors resulting from the crystallization of (+)-(S)clopidogrel hydrogen sulfate Form 1 contain 0.3 to 1% water. 8. Fremgangsmåte som angitt i krav 6, hvor de vandige acetonholdige modervæsker resulterende fra krystalliseringen av (+)-(S)-clopidogrel-hydrogensulfat Form 1 inneholder opptil omtrent 10 % clopidogrel-hydrogensulfat, hvor denne mengde beregnes ut fra mengden metyl ( + ) - (S)-os-(2-klorfenyl) - 4,5,6,7-tetrahydrotieno[3,2-c]pyridinyl-5-acetatkamfersulfonat som anvendes under omdannelsen til hydrogensulfat.8. Process as stated in claim 6, where the aqueous acetone-containing mother liquors resulting from the crystallization of (+)-(S)-clopidogrel hydrogen sulfate Form 1 contain up to approximately 10% clopidogrel hydrogen sulfate, where this amount is calculated from the amount of methyl ( + ) - (S)-os-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl-5-acetate camphorsulfonate which is used during the conversion to hydrogen sulfate. 9. Fremgangsmåte som angitt i ett eller flere av kravene 6 - 8, hvor de vandige acetonholdige modervæsker som resulterer fra krystalliseringen av (+)-(S) clopidogrel-hydrogensulfat Form 1 frigjør sakte, etter en periode på fra 3 til 6 måneder, ved en temperatur på mindre enn 40 °C, clopidogrel-hydrogensulf at Form 2.9. Process as stated in one or more of claims 6 - 8, where the aqueous acetone-containing mother liquors resulting from the crystallization of (+)-(S) clopidogrel hydrogen sulfate Form 1 release slowly, after a period of from 3 to 6 months, at a temperature of less than 40 °C, clopidogrel hydrogen sulph at Form 2. 10. Fremgangsmåte for fremstilling av clopidogrel-hydrogen-sulf at Form 2 hvor: (a) metyl (+)-(S)-a-(2-klorfenyl)-4,5,6,7-tetrahydrotieno-[3,2-c]pyridinyl-5-acetatkamfersulfonat oppløses i et organisk løsningsmiddel, (b) kamfersulfonsyre ekstraheres med en vandig alkalisk oppløsning av kaliumkarbonat og vaskes med vann, (c) den organiske fase konsentreres under redusert trykk og konsentrasjonsresten tas opp i aceton, karakterisert ved at 94 -96% svovelsyre tilsettes og at blandingen podes med clopidogrel-hydrogen-sulf at Form 2, produktet krystalliseres, blandingen avkjøles, filtreres og krystallene vaskes og tørkes deretter under redusert trykk til å gi clopidogrel-hydrogensulfat Form 2.10. Process for the production of clopidogrel hydrogen sulfate Form 2 where: (a) methyl (+)-(S)-a-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno-[3,2 -c]pyridinyl-5-acetate camphorsulfonate is dissolved in an organic solvent, (b) camphorsulfonic acid is extracted with an aqueous alkaline solution of potassium carbonate and washed with water, (c) the organic phase is concentrated under reduced pressure and the concentration residue is taken up in acetone, characterized in that 94 -96% sulfuric acid is added and that the mixture is seeded with clopidogrel hydrogen sulphate Form 2, the product is crystallized, the mixture is cooled, filtered and the crystals are then washed and dried under reduced pressure to give clopidogrel hydrogen sulphate Form 2. 11. Farmasøytisk preparat, karakterisert ved at det som aktiv bestanddel inneholder Form 2-polymorfen av clopidogrel-hydrogensulfat som angitt i krav 1 i kombinasjon med minst ett farmasøytisk hjelpestoff.11. Pharmaceutical preparation, characterized in that it contains as an active ingredient the Form 2 polymorph of clopidogrel hydrogen sulfate as stated in claim 1 in combination with at least one pharmaceutical excipient.
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